Constipation affects up to 20% of the US population, mainly women and the elderly. Affected individuals experience impaired quality of life and most are dissatisfied with current therapy. Our long-term goals are to develop therapies that remedy the underlying multifactorial dysfunction(s), and elucidate their neurobiologic and mechanistic bases. Through the previous application, we showed that biofeedback improved dyssynergic defecation and led to superior patient satisfaction. Here we aim to test new behavioral treatments for other dysfunctions and by integrating this with mechanistic studies we can reveal how the brain and the gut (gut- brain axis) interact, and how biofeedback modulates cortico-rectal function. We propose four specific aims: 1) Currently, biofeedback therapy requires a skilled therapist to train a patient using sophisticated equipment in a physiologic laboratory. We developed and tested a battery powered device for patients to use in their own home. We will determine if a community-based biofeedback therapy is as effective as laboratory- based biofeedback therapy. We will investigate and compare the efficacy, costs and outcomes of 100 patients with dyssynergic defecation, randomized to either home therapy or office-based therapy. 2) Our preliminary studies revealed that gut-brain function is deranged in dyssynergic patients, compared to controls and that biofeedback restores normal function. We will investigate the integrity of anorectal-brain interactions in 50 dyssynergic subjects (before and after biofeedback) and compare this with 25 healthy controls by measuring the cortical evoked potentials (CEP) after electrical stimulation of the anorectum (afferent) and the motor evoked potentials (MEP) following transcranial magnetic stimulation (efferent). 3) Currently, sensory conditioning of a hyposensitive rectum involves repetetive filling of a balloon with a hand-held syringe;this awkward approach reduces its effectiveness. We will test, in a randomized study, if barostat (pressure-driven computerized system) training is superior to syringe-assisted sensory training, in 70 constipated subjects with rectal hyposensitivity. Also, we will examine the neuroenteric mechanism(s) of rectal hyposensitivity by investigating anorectal sensori-motor function as well as CEPs and MEPs, before and after sensory training, and elucidate the locus (central versus peripheral) for neuronal modulation. 4) Constipation accompanied by abdominal pain is commonly associated with rectal hypersensitivity, a condition with no effective therapy. We developed and tested a new behavioral therapy, comprising of sensory adaptation training (SAT) using a barostat. In a RCT, we will compare SAT with escitalopram, a SSRI, in 60 constipated IBS patients and test its efficacy in reducing pain and improving hypersensitivity. These studies aim to define the mechanisms of, and evaluate new therapies for dyssynergia, rectal hyposensitivity and rectal hypersensitivity, and could significantly impact constipation treatments.